Novel glutamic acid derived cholecystokinin receptor ligands.
Novel aryl amide analogues of glutamic acid dialkylamide have been synthesized to test for a possible structural analogy between glutamic acid and benzodiazepine CCK antagonists such as compounds 2 and 24 (lorglumide and MK-329, respectively). In support of the structural model, certain of these hybrid compounds are more potent in pancreas CCK radioligand binding assays than corresponding lorglumide-type reference compounds. Modifications previously found in the benzodiazepine antagonists to result in brain CCK/gastrin receptor selectivity were also incorporated to produce an aryl urea series of glutamic acid analogues. None of these compounds were brain CCK/gastrin selective; however, one was potent and selective in the pancreas binding assay. The model appears to be most useful in the design of selective ligands for the pancreas type CCK receptor.
Freidinger
R M
RM
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Whitter
W L
WL
Gould
N P
NP
Holloway
M K
MK
Chang
R S
RS
Lotti
V J
VJ
D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000378:metabolism; D003196:Computer Graphics; D005971:Glutamates; D006168:Guinea Pigs; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005971:Glutamates; D008024:Ligands; D011949:Receptors, Cholecystokinin; D002766:Cholecystokinin